This invention relates to a novel class of compounds which exhibit analgesic activity upon parenteral administration.
Recently, endogenous substances having morphine-like properties have been extracted from mammalian brain or csf. These substances, named enkephalin, have been identified by Hughes et al., Nature, 258, 577 (1975) as pentapeptides having the following sequences:
H-Tyr-Gly-Gly-Phe-Met-OH PA1 H-Tyr-Gly-Gly-Phe-Leu-OH. PA1 Abu--.alpha.-aminobutyric acid PA1 Ala--alanine PA1 Cys--cysteine PA1 Gly--glycine PA1 Hse--homoserine PA1 Ile--isoleucine PA1 Leu--leucine PA1 Met--methionine PA1 Nle--norleucine PA1 Nva--norvaline PA1 Phe--phenylalanine PA1 Ser--serine PA1 Thr--threonine PA1 Tyr--tyrosine PA1 Val--valine PA1 Ac--acetyl PA1 Me--methyl PA1 Et--ethyl PA1 Ip--isopropyl PA1 Pr--n-propyl PA1 Bu--n-butyl PA1 i-Bu--isobutyl PA1 t-Bu--t-butyl PA1 s-Bu--sec-butyl PA1 BOC--t-butyloxycarbonyl PA1 Bzl--benzyl PA1 DCC--N,N'-dicyclohexylcarbodiimide PA1 HBT--1-hydroxybenzotriazole PA1 DMF--N,N-dimethylformamide PA1 TFA--trifluoroacetic acid PA1 THF--tetrahydrofuran PA1 DEAE--diethylaminoethyl PA1 H-L-Tyr-D-Ala-Gly-L-Phe-D,L-(.alpha.-Me)Met-NH.sub.2 ; PA1 H-L-Tyr-D-Met-Gly-L-Phe-D,L-(.alpha.-Me)Met-NH.sub.2 ; PA1 H-L-Tyr-D-Ser-Gly-L-Phe-L-(.alpha.-Me)Met-NH.sub.2 ; PA1 H-L-Tyr-D-Abu-Gly-L-Phe-L-(.alpha.-Et)Met-NH.sub.2 ; PA1 H-L-Tyr-D-Thr-Gly-L-Phe-D-(.alpha.-Me)Met-NH.sub.2 ; PA1 H-L-Tyr-D-Nva-Gly-L-Phe-L-(.alpha.-Me)Met-NH.sub.2 ; PA1 H-L-Tyr-D-Val-Gly-L-Phe-L-(.alpha.-Me)Met-NH.sub.2 ; PA1 H-L-Tyr-D-Hse-Gly-L-Phe-D,L-(.alpha.-Pr)Met-NH.sub.2 ; PA1 H-L-Tyr-D-Nle-Gly-L-Phe-(.alpha.-Me)Met-NH.sub.2 ; PA1 H-L-Tyr-D-Nle-Gly-L-Phe-L-(.alpha.-Et)Met-NH.sub.2 ; PA1 H-L-Tyr-D-Leu-Gly-L-Phe-L-(.alpha.-Me)Met-NH.sub.2 ; PA1 H-L-Tyr-D-Hse(Me)-Gly-L-Phe-L-(.alpha.-Pr)Met-NH.sub.2 ; PA1 H-L-Tyr-D-Ile-Gly-L-Phe-L-(.alpha.-Me)Met-NH.sub.2 ; PA1 H-L-Tyr-D-Ile-Gly-L-Phe-L-(.alpha.-Pr)Met-NH.sub.2 ; PA1 H-L-Tyr-D-Ala-Gly-L-Phe-L-(.alpha.-Et)Met-NH.sub.2 ; PA1 H-L-Tyr-D-Ser-Gly-L-Phe-L-(.alpha.-Pr)Met-NH.sub.2 : PA1 H-L-Tyr-D-Ala-Gly-L-Phe-L-(.alpha.-Pr)Met-NH.sub.2 ; PA1 H-L-Tyr-D-Ala-Gly-L-Phe-L-(.alpha.-Me)Met-CH.sub.2 OH; PA1 H-L-Tyr-D-Ala-Gly-L-Phe-L-(.alpha.-Et)Met-CH.sub.2 OH; PA1 H-L-Tyr-D-Ala-Gly-L-Phe-L-(.alpha.-Me)Met-CH.sub.2 OH; PA1 H-L-Tyr-D-Ala-Gly-L-Phe-D-(.alpha.-Pr)Met-CH.sub.2 OH; PA1 H-L-Tyr-D-Met-Gly-L-Phe-L-(.alpha.-Et)Met-CH.sub.2 OH; PA1 H-L-Tyr-D-Val-Gly-L-Phe-L-(.alpha.-Me)Met-CH.sub.2 OH; PA1 H-L-Tyr-D-Leu-Gly-L-Phe-L-(.alpha.-Me)Met-CH.sub.2 OH; PA1 H-L-Tyr-D-Val-Gly-L-Phe-L-(.alpha.-Et)Met-CH.sub.2 OH; PA1 H-L-Tyr-D-Leu-Gly-L-Phe-D-(.alpha.-Me)Met-CH.sub.2 OH; PA1 H-L-Tyr-D-Ala-Gly-L-Phe-D,L-(.alpha.-Me)Nle-NH.sub.2 ; PA1 H-L-Tyr-D-Ala-Gly-L-Phe-L-(.alpha.-Me)Hse(Me)-NH.sub.2 ; PA1 H-L-Tyr-D-Ala-Gly-L-Phe-L-(.alpha.-Me)Nle-NH.sub.2 ; PA1 H-L-Tyr-D-Ala-Gly-L-Phe-L-(.alpha.-Me)Hse(Me)-NH.sub.2 ; PA1 H-L-Tyr-D-Ser-Gly-L-Phe-L-(.alpha.-Et)Met-NH.sub.2 ; PA1 H-L-Tyr-D-Hse-Gly-L-Phe-L-(.alpha.-Me)Met-NH.sub.2 ; PA1 H-L-Tyr-D-Thr-Gly-L-Phe-L-(.alpha.-Me)Met-NH.sub.2 ; PA1 H-L-Tyr-D-Hse(Me)-Gly-L-Phe-L-(.alpha.-Me)Met-CH.sub.2 OH; PA1 H-L-Tyr-D-Ser-Gly-L-Phe-L-(.alpha.-Me)Met-NH.sub.2 ; PA1 H-L-Tyr-D-Met-Gly-L-Phe-L-(.alpha.-Me)Met-CH.sub.2 OH; PA1 H-L-Tyr-D-Ser-Gly-L-Phe-L-(.alpha.-Me)Nle-CH.sub.2 OH; PA1 H-L-Tyr-D-Met-Gly-L-Phe-L-(.alpha.-Me)Hse(Me)-NH.sub.2 ; PA1 H-L-Tyr(Ac)-D-Ala-Gly-L-Phe-D,L-(.alpha.-Et)Met-NH.sub.2 ; PA1 H-L-Tyr(Ac)-D-Ala-Gly-L-Phe-D,L-(.alpha.-Me)Met-NH.sub.2 ; PA1 H-L-Tyr-D-Nle-Gly-L-Phe-D-(.alpha.-Me)Met-CH.sub.2 OH; PA1 H-L-Tyr-D-Abu-Gly-L-Phe-D-(.alpha.-Me)Met-CH.sub.2 OH; PA1 (N-Me)-L-Tyr-D-Ala-Gly-L-Phe-D,L-(.alpha.-Me)Met-NH.sub.2 ; PA1 (N,N-Di-Me)-L-Tyr-D-Ala-Gly-L-Phe-D,L-(.alpha.-Me)-Met-NH.sub.2 ; PA1 (N-Pr)-L-Tyr-D-Ala-Gly-L-Phe-D,L-(.alpha.-Me)Met-NH.sub.2 ; PA1 (N-Et)-L-Tyr-D-Abu-Gly-L-Phe-D,L-(.alpha.-Et)Nle-NH.sub.2 ; PA1 (N,N-di-Pr)-L-Tyr-D-Val-Gly-L-Phe-D,L-(.alpha.-Me)-Hse(Me)-NH.sub.2 ; PA1 (N-Pr)-L-Tyr-D-Leu-Gly-L-Phe-D-(.alpha.-Me)Met-NH.sub.2 ; PA1 (N,N-Di-Et)-L-Tyr-D-Abu-Gly-L-Phe-D,L-(.alpha.-Et)-Met-NH.sub.2 ; PA1 (N-Me,N-Et)-L-Tyr(Ac)-D-Nle-Gly-L-Phe-D,L-(.alpha.-Me)Met-NH.sub.2 ; PA1 (N,N-Di-Me)-L-Tyr(Ac)-D-Ile-Gly-L-Phe-L-(.alpha.-Pr)-Met-NH.sub.2 ; PA1 (N-Me)-L-Tyr(Ac)-D-Leu-Gly-L-Phe-L-(.alpha.-Et)Nle-NH.sub.2 ; PA1 (N-Me)-L-Tyr(Ac)-D-Nva-Gly-L-Phe-D-(.alpha.-Me)Hse-(Me)-NH.sub.2 ; PA1 H-L-Tyr-D-Ser-Gly-L-Phe-D,L-(.alpha.-Pr)Met-CH.sub.2 OH; PA1 H-L-Tyr-D-Thr-Gly-L-Phe-D,L-(.alpha.-Me)Met-CH.sub.2 OH; PA1 H-L-Tyr-D-Ala-Gly-L-Phe-D,L-(.alpha.-Me)Nle-CH.sub.2 OH; PA1 H-L-Tyr-D-Hse-Gly-L-Phe-D,L-(.alpha.-Me)Hse(Me)-CH.sub.2 OH; PA1 H-L-Tyr-D-Ala-Gly-L-Phe-L-(.alpha.-Me)Met-NH(Me); PA1 H-L-Tyr-D-Ala-Gly-L-Phe-D,L-(.alpha.-Me)Met-NH(Me); PA1 H-L-Tyr-D-Ala-Gly-L-Phe-L-(.alpha.-Et)Met-NH(Me); PA1 H-L-Tyr-D-Ala-Gly-L-Phe-D,L-(.alpha.-Me)Met-NH(Et); PA1 H-L-Tyr-D-Ala-Gly-L-Phe-D,L-(.alpha.-Et)Met-NH(Et); PA1 H-L-Tyr-D-Ala-Gly-L-Phe-D-(.alpha.-Me)Nle-NH(Me); PA1 H-L-Tyr-D-Ala-Gly-L-Phe-D-(.alpha.-Et)Met-NH(Pr); PA1 H-L-Tyr-D-Ala-Gly-L-Phe-L-(.alpha.-Pr)Met-NH(Me); PA1 H-L-Tyr-D-Nle-Gly-L-Phe-D-(.alpha.-Me)Met-NH(Pr); PA1 (N,N-Di-Me)-L-Tyr-D-Ala-Gly-L-Phe-L-(.alpha.-Me)Met-NH(Et); PA1 (N,N-Di-Me)-L-Tyr-D-Nle-Gly-L-Phe-D,L-(.alpha.-Me)Met-CH.sub.2 OH; PA1 (N,N-Di-Et)-L-Tyr-D-Nva-Gly-L-Phe-L-(.alpha.-Et)Met-NH(Me); PA1 (N-Pr)-L-Tyr-D-Abu-Gly-L-Phe-D,L-(.alpha.-Me)Nle-NH(Me); PA1 (N-Me)-L-Tyr-D-Ala-Gly-L-Phe-D,L-(.alpha.-Pr)Hse(Me)-NH(Me); PA1 (N,N-Di-Me)-L-Tyr-D-Val-Gly-L-Phe-L-(.alpha.-Me)Met-NH(Me); PA1 (N,N-Di-Pr)-L-Tyr-D-Ala-Gly-L-Phe-L-(.alpha.-Me)Met-NH(Me); PA1 (N,N-Di-Me)-L-Tyr(Ac)-D-Ala-Gly-L-Phe-D,L-(.alpha.-Me)Met-NH(Me); PA1 (N,N-Di-Pr)-L-Tyr(Ac)-D-Val-Gly-L-Phe-D,L-(.alpha.-Me)Met-NH(Me); PA1 (N-Pr)-L-Tyr(Ac)-D-Ile-Gly-L-Phe-D,L-(.alpha.-Pr)Nle-NH(Et); PA1 (N-Me)-L-Tyr(Ac)-D-Leu-Gly-L-Phe-D,L-(.alpha.-Me)Hse-(Me)-NH(Pr); PA1 H-L-Tyr-D-Ala-Gly-L-Phe-D-(.alpha.-Me)Ser(Et)-NH.sub.2 ; PA1 H-L-Tyr-D-Ala-Gly-L-Phe-L-(.alpha.-Me)Leu-NH.sub.2 ; PA1 H-L-Tyr-D-Abu-Gly-L-Phe-L-(.alpha.-Me)Cys(p-methoxy-Bzl)-NH.sub.2 ; PA1 H-L-Tyr-D-Abu-Gly-L-Phe-D,L-(.alpha.-Me)Leu-CH.sub.2 OH; PA1 H-L-Tyr-D-Nva-Gly-L-Phe-D,L-(.alpha.-Et)Leu-NH.sub.2 ; PA1 H-L-Tyr-D-Nva-Gly-L-Phe-D,L-(.alpha.-Et)Ser(p-methoxy-Bzl)-NH.sub.2 ; PA1 H-L-Tyr-D-Val-Gly-L-Phe-D,L-(.alpha.-Me)Leu-NH.sub.2 ; PA1 H-L-Tyr-D-Val-Gly-L-Phe-L-(.alpha.-Me)Ser(Me)-NH.sub.2 ; PA1 H-L-Tyr-D-Nle-Gly-L-Phe-L-(.alpha.-Me)Cys(Me)-NH.sub.2 ; PA1 H-L-Tyr-D-Nle-Gly-L-Phe-D,L-(.alpha.-Et)Leu-NH.sub.2 ; PA1 H-L-Tyr-D-Leu-Gly-L-Phe-D,L-(.alpha.-Me)Ser(Bzl)-NH.sub.2 ; PA1 H-L-Tyr-D-Leu-Gly-L-Phe-D,L-(.alpha.-Pr)Leu-NH.sub.2 ; PA1 H-L-Tyr-D-Ile-Gly-L-Phe-L-(.alpha.-Pr)Cys(Bzl)-NH.sub.2 ; PA1 H-L-Tyr-D-Ile-Gly-L-Phe-D-(.alpha.-Pr)Leu-CH.sub.2 OH; PA1 H-L-Tyr-D-Ala-Gly-L-Phe-D,L-(.alpha.-Et)Leu-NH.sub.2 ; PA1 H-L-Tyr-D-Ala-Gly-L-Phe-D,L-(.alpha.-Pr)Leu-NH.sub.2 ; PA1 H-L-Tyr-D-Ala-Gly-L-Phe-D,L-(.alpha.-Pr)Leu-CH.sub.2 O; PA1 H-L-Tyr-D-Ala-Gly-L-Phe-L-(.alpha.-Pr)Ser(Pr)-NH.sub.2 ; PA1 H-L-Tyr-D-Ala-Gly-L-Phe-D-(.alpha.-Et)Leu-CH.sub.2 OH; PA1 H-L-Tyr-D-Ala-Gly-L-Phe-D,L-(.alpha.-Me)Ser(Ip)-NH.sub.2 ; PA1 H-L-Tyr-D-Nle-Gly-L-Phe-D,L-(.alpha.-Et)Leu-CH.sub.2 OH; PA1 H-L-Tyr-D-Ala-Gly-L-Phe-D,L-(.alpha.-Me)Cys(i-Bu)-NH.sub.2 ; PA1 H-L-Tyr-D-Val-Gly-L-Phe-D,L-(.alpha.-Me)Leu-CH.sub.2 OH; PA1 H-L-Tyr-D-Leu-Gly-L-Phe-D,L-(.alpha.-Me)Leu-CH.sub.2 OH; PA1 H-L-Tyr-D-Val-Gly-L-Phe-L-(.alpha.-Et)Leu-CH.sub.2 OH; PA1 H-L-Tyr-D-Ala-Gly-L-Phe-L-(.alpha.-Me)Ser(p-methoxy-Bzl)-NH.sub.2 ; PA1 H-L-Tyr-D-Ala-Gly-L-Phe-D-(.alpha.-Pr)Cys(Et)-NH.sub.2 ; PA1 H-L-Tyr-D-Ala-Gly-L-Phe-D-(.alpha.-Me)Ser(Et)-NH.sub.2 ; PA1 H-L-Tyr-D-Ala-Gly-L-Phe-D,L-(.alpha.-Me)Cys(Et)-NH.sub.2 ; PA1 H-L-Tyr-D-Ala-Gly-L-Phe-D,L-(.alpha.-Et)Ser(Et)-CH.sub.2 OH; PA1 H-L-Tyr-D-Ala-Gly-L-Phe-D,L-(.alpha.-Me)Cys(Et)-CH.sub.2 OH; PA1 H-L-Tyr-D-Ile-Gly-L-Phe-D,L-(.alpha.-Me)Ser(p-chloro-Bzl)-NH.sub.2 ; PA1 H-L-Tyr(Ac)-D-Ala-Gly-L-Phe-D,L-(.alpha.-Me)Ser(m-trifluoromethyl-Bzl)-NH.s ub.2 ; PA1 H-L-Tyr(Ac)-D-Ala-Gly-L-Phe-D,L-(.alpha.-Me)Leu-CH.sub.2 OH; PA1 H-L-Tyr-D-Nle-Gly-L-Phe-D,L-(.alpha.-Me)Cys(o-methyl-Bzl)-NH.sub.2 ; PA1 H-L-Tyr-D-Abu-Gly-L-Phe-L-(.alpha.-Me)Leu-CH.sub.2 OH; PA1 (N-Me)-L-Tyr-D-Ala-Gly-L-Phe-D-(.alpha.-Pr)Ser(p-methoxy-Bzl)-NH.sub.2 ; PA1 (N,N-Di-Me)-L-Tyr-D-Ala-Gly-L-Phe-D,L-(.alpha.-Me)-Leu-CH.sub.2 OH; PA1 (N-Et)-L-Tyr-D-Abu-Gly-L-Phe-D,L-(.alpha.-Et)Leu-NH.sub.2 ; PA1 (N,N-di-Pr)-L-Tyr-D-Val-Gly-L-Phe-D,L-(.alpha.-Me)-Leu-NH.sub.2 ; PA1 (N-Pr)-L-Tyr-D-Leu-Gly-L-Phe-D,L-(.alpha.-Me)Leu-NH.sub.2 ; PA1 (N,N-Di-Et)-L-Tyr-D-Abu-Gly-L-Phe-D,L-(.alpha.-Me)-Leu-NH.sub.2 ; PA1 (N-Me,N-Et)-L-Tyr(Ac)-D-Nle-Gly-L-Phe-D,L-(.alpha.-Me)Leu-NH.sub.2 ; PA1 (N,N-Di-Me)-L-Tyr(Ac)-D-Ile-Gly-L-Phe-D,L-(.alpha.-Pr)Leu-NH.sub.2 ; PA1 (N-Me)-L-Tyr(Ac)-D-Leu-Gly-L-Phe-L-(.alpha.-Et)D,L-Leu-NH.sub.2 ; PA1 (N-Me)-L-Tyr(Ac)-D-Nva-Gly-L-Phe-D,L-(.alpha.-Me)Ser(t-Bu)-NH.sub.2 ; PA1 H-L-Tyr-D-Ala-Gly-L-Phe-L-(.alpha.-Et)Ser(s-Bu)-NH.sub.2 ; PA1 H-L-Tyr-D-Abu-Gly-L-Phe-D,L-(.alpha.-Me)Leu-NH.sub.2 ; PA1 H-L-Tyr-D-Ala-Gly-L-Phe-D,L-(.alpha.-Me)Cys(p-methoxy-Bzl)-NH.sub.2 ; PA1 H-L-Tyr-D-Ala-Gly-L-Phe-D-(.alpha.-Me)Ser(Et)-NH.sub.2 ; PA1 H-L-Tyr-D-Ala-Gly-L-Phe-L-(.alpha.-Me)Ser(Et)-NH(Me); PA1 H-L-Tyr-D-Ala-Gly-L-Phe-D,L-(.alpha.-Me)Leu-NH(Me); PA1 H-L-Tyr-D-Ala-Gly-L-Phe-D,L-(.alpha.-Et)Leu-NH(Me); PA1 H-L-Tyr-D-Ala-Gly-L-Phe-D,L-(.alpha.-Me)Leu-NH(Et); PA1 H-L-Tyr-D-Ala-Gly-L-Phe-D,L-(.alpha.-Et)Leu-NH(Et); PA1 H-L-Tyr-D-Ala-Gly-L-Phe-D,L-(.alpha.-Et)Cys(p-bromo-Bzl)-NH(Pr); PA1 H-L-Tyr-D-Ala-Gly-L-Phe-D,L-(.alpha.-Pr)Leu-NH(Me); PA1 H-L-Tyr-D-Ala-Gly-L-Phe-L-(.alpha.-Me)Cys(Ip)-NH(Pr); PA1 (N,N-Di-Me)-L-Tyr-D-Ala-Gly-L-Phe-D,L-(.alpha.-Me)Leu-NH(Et); PA1 (N,N-Di-Me)-L-Tyr-D-Ala-Gly-L-Phe-D,L-(.alpha.-Me)Leu-NH.sub.2 ; PA1 (N,N-Di-Et)-L-Tyr-D-Ala-Gly-L-Phe-D,L-(.alpha.-Et)-Leu-NH(Me); PA1 (N-Pr)-L-Tyr-D-Ala-Gly-L-Phe-D,L-(.alpha.-Me)Leu-NH(Me); PA1 (N-Me)-L-Tyr-D-Ala-Gly-L-Phe-D,L-(.alpha.-Pr)Ser(Bzl)-NH(Me); PA1 (N,N-Di-Me)-L-Tyr-D-Val-Gly-L-Phe-D,L-(.alpha.-Me)Leu-NH(Me); PA1 (N,N-Di-Pr)-L-Tyr-D-Ala-Gly-L-Phe-D,L-(.alpha.-Me)-Leu-NH-(Me); PA1 H-L-Tyr-D-Ala-Gly-L-Phe-D,L-(.alpha.-Me)Ser(Pr)-NH(Me); PA1 (N,N-Di-Me)-L-Tyr(Ac)-D-Ala-Gly-L-Phe-D,L-(.alpha.-Me)Leu-NH(Me); PA1 (N,N-Di-Pr)-L-Tyr(Ac)-D-Val-Gly-L-Phe-D,L-(.alpha.-Me)Leu-NH(Me); PA1 (N-Pr)-L-Tyr(Ac)-D-Ile-Gly-L-Phe-D,L-(.alpha.-Pr)Leu-NH(Et); PA1 (N-Me)-L-Tyr(Ac)-D-Leu-Gly-L-Phe-D,L-(.alpha.-Me)Leu-NH(Pr);
These compounds are referred to as methionine-enkephalin and leucine-enkephalin, respectively.
Although these compounds have been shown to exhibit analgesic activity in mice upon administration intracerebroventricularly [Buscher et al., Nature, 261, 423 (1976)], they are practically devoid of any useful analgesic activity when administered parenterally.
Since the discovery of the enkephalins, much effort has been devoted to preparing analogs of the enkephalins in the hope of finding compounds having enhanced activity and practical utility due to their bioavailability by parenteral or oral administration.
Dutta et al., Life Sciences 21, pp. 559-562 (1977) report certain structure modifications which, they suggest, tend to enhance potency. They suggest activity can be enhanced by any or all of the following:
(a) substitution of Gly in position 2 by certain D- or .alpha.-aza-amino acids;
(b) conversion of the terminal carboxyl by esterification to the methyl ester or the amide;
(c) modification of the Phe in the 4-position by .alpha.-aza substitution, N-methylation, or hydrogenation of the aromatic ring.
In addition, Roemer et al., Nature 268, pp. 547-549 (1977), suggest modification of the Met.sup.5 to its corresponding carbinol and oxidation of the Met sulfur to the sulfoxide as useful modifications.
Another structural modification of significance is that reported in Belgian Pat. No. 859,026. This publication suggests enhancement of activity and bioavailability of enkephalin analogs by insertion of a D-amino acid residue in position 2, conversion of the terminal carboxyl to an amide, and N-alkylation of the amino acid residue in position 5.
A further novel class of compounds has now been discovered. These compounds exhibit significant and demonstrable analgesic activity when administered systemically. The compounds also are useful in the amelioration of emotional disease. It is to this class of compounds that this invention is directed.